Discussion of possible causes of cancer. ---- Background: Unusual characteristics of tumor cells: * genetically unstable * undergo reverse differentiation * fail to undergo apoptosis in response to damage or signalling * cells grow and divide independently (in the absence of growth signals and despite the presence of growth inhibitors such as cell-to-cell contact, maturation/differentiation signals, etc) * cells become immortal, avoid senescence (no Hayflick limit on maximum number of divisions; telomerase used to extend length of telomeres at ends of chromosomes) * angiogenesis: tumor cells stimulate the growth of new blood vessels to feed them, allowing them to grow faster and to better spread to other parts of the body * structural changes to allow greater mobility (changes in cells' microfilaments and microtubules) * decreased adhesion to neighboring cells and extracellular matrix to increase mobility * enzyme production to digest barriers to invasion of neighboring cells ---- This might be a good place to insert the recent hypothesis that cancers, all cancers, have their roots in chromosomal damage and that a ''generic'' treatment for cancer (a genuine 'cure for cancer') can indeed be developed. This would be a far cry from the current fragmentation of research and treatment efforts. * The Knudson Hypothesis about multiple genetic mutation to inactivate tumor suppressor genes was proposed in 1971 and verified at the molecular level with the inheritance of single defective copies of the retinablastoma gene in 1976. It is certain now that cancer is a molecular disease that can be caused by accumulated mutations (sequence damage). ''Another hypothesis rotates that view 90 degrees: that all cancer is caused by viruses, exacerbated by damage to genetic structures that would otherwise assist in resisting the virus. Prototypical tumors have characteristics that match many of those on the usual attempts at checklists of what defines "life".'' ''If you look at the list of characteristics of tumor cells I added to the top of the page, it is immediately evident that every single one of those characteristics is highly functional, as if the tumor cells were carefully designed to spread, as if they were a separate organism from (or parasite on) the host.'' ''It is patently absurd to suppose that such wonderful design, in toto, should seriously be considered "damage". A damaged cell tends to function worse than before. These cancer cells are functioning '''better''' than before - albeit at a cost to the host organism.'' * It is not the case that all cancer is viral in origin as clonally-derived mice kept in pathogen-free environments still develop cancer. That viruses can be contributing factors in the development of cancer is well established (see below) and was proposed at least 50 years ago (for what it's worth if you hear him talk, JamesWatson believes he deserves the credit for this idea). ** For one thing, we do not have the technology to be 100% sure that viruses are 100% excluded from any environment. For another thing, these mice may well have oncogenetic materials from viruses already incorporated into their genome. * It's not absurd because the "wonderful design" is for the most part a state similar to protozoa, which animals evolved from. It might be possible to blame oncogenetic materials, but those are extremely widespread, and possibly may have become integral parts in the function of our cells. Since the best current hypothesis for the origin of viruses is as cellular DNA that became an independent parasite, akin to prions, it doesn't seem a meaningful distinction. In any case, this 100% stuff is a red herring. Wouldn't these studies ''strongly suggests'' cancer isn't always viral? * Well, that's all true. I don't see how to explain angiogenesis very well that way, though. ''Continued below.'' * Oh...also I've seen conflicting reports in, and since, the human genome project report in Nature, about the amount of DNA in humans that appears to be from extra-species sources such as viruses and bacteria -- I used to think there was lots and lots, but now there are some claims that there is actually fairly little. Do you know the latest on this? hmm... Is there any evidence for that hypothesis? As far as I know, there is no evidence for cancers being caused by viruses. The best current evidence suggests that cancers are cellular reproduction processes gone haywire, as opposed to cellular reproduction taken over by a virus (or other foreign organism). Viruses could cause this indirectly, by inserting themselves into genes at inopportune places. For example, if a virus inserts itself in a gene coding for DNA repair, it can cause DNA repair to go faulty. The damage caused to cellular reproduction in this manner is no different from any other damage to cells. -- AlexAusch Person2: 'Cellular reproduction mechanisms gone haywire' is the definition of cancer, not its actual cause. At least, not for researchers trying to look beyond Cancer 1234-B. There's plenty of evidence for cancers being caused by viruses, though I don't know how general that is. Could you point me to some of this evidence? The only evidence I've seen was for a non cause-effect type relationship. I've read some about this, and all that I've read suggests that, when it happens that a virus is the ultimate cause for cancer in a specific patient, it's like a case of a straw breaking the camel's back. That is: (1) the virus isn't cancer causing, but has some other effect, which, accumulated with other DNA damage, causes cancer (2) if the virus wasn't going to do it, something else would have - the type of damage caused by the virus can be caused by a large variety of factors (radiation, certain chemicals, etc...) * ''Evidence? You betcha. Second hit on google search of "virus cancer": "For nearly 100 years, viruses have been suspects in the mystery of how cells become cancerous". http://www.asco.org/ac/1,1003,_12-002210-00_18-0032309-00_19-00-00_20-001,00.asp'' * ''Next: conference on virus/cancer link: http://www.fhcrc.org/pubs/center_news/2000/Nov2/virus.sht'' * ''http://www.ghanaweb.com/GhanaHomePage/NewsArchive/artikel.php?ID=57110'' * ''Then I searched for very recent news; the human papilloma virus link to cervical cancer: http://www.nbc5i.com/family/3032157/detail.html http://www.ghanaweb.com/GhanaHomePage/NewsArchive/artikel.php?ID=57110'' * ''Or how about the Hepatitus-B virus and liver cancer link: http://www.medicalnewstoday.com/index.php?newsid=8047'' * Also Epstein-Barr virus and Karposi's sarcoma, common in AIDS patients. * ''That's just the tip of the iceberg; there's lots more, of course.'' This means that preventing the viral infection will not prevent the cancer from happening, it will only slow down its progress. (ie, it's not a direct cause-effect relationship, but a probabilistic one. Certain types of viruses cause DNA damage, and thus increase the probability of cancer occurrence. This is a weaker statement than the statement: certain types of viruses cause cancer. And it's even weaker than saying: certain viruses cause cancer). -- AlexAusch No; you are speculating (although I think that was by far the majority speculation 3 decades ago), but I think that evidence is overwhelming in the other direction now. See my above comment about tumors fitting the definition of life; that practically makes the link derivable from first principles (not that anything in biology is susceptible to that. ;-) -- DougMerritt ''Not if a part of a living thing can become an independent organism, the suggested origin of tumors and viruses alike.'' * But for it to not only become independent, but to be aggressively successful, requires evolution to acquire those amazingly successful traits. It is not an explanation to say that it just happens to be that way after severe damage. * It could be a statistical thing, though. Some cancers are benign, they just form small growths and then die out. Many damaged cells never even make it that far. Since a successful cancer will show up so much more prominently than any other form of cellular damage, all you need is for such mutations to be possible. ''If'' the traits are generally protozoan or at least simple, that's not implausible. I don't know how simple angiogenesis is to effect, mind. Let's localize discussion on that below. The case of papilloma virus and its involvement in cervical cancer is interesting. The virus doesn't directly damage DNA by itself but it encodes for two proteins (E6 and E7) which find the cell's master cell-cycle control protein p53 and target it for protein-mediated destruction. Thus, even though the infected cells are genotypically p53+/+, they are phenotypically p53 negative. This puts the infected cervical cells into a hyper-proliferative state (which helps the virus divide). At this point the cells are pre-cancerous, but not actually cancerous since they still can't grow in crowded conditions and can't detach to metastasize throughout the body. They show up nicely on a pap-smear and can be removed either surgically or with laser treatment. If not removed, they become ''susceptible'' to picking up the additional chromosomal mutations that transform them from pre-cancerous to cancerous although it is by no means certain that they will make this transition, which is to say that not all people with an untreated cervical papilloma infection will develop cervical cancer, just significantly more than a matched set of uninfected people would. The HeLa cell line was established in 1951 from the cervical cancer cells of a patient who later died of the disease (31-year-old '''He'''nrietta '''La'''cks - dies 8 months post-diagnosis). These cells are still in culture and going strong today. They don't have infectious papillomavirus in them anymore, but they still do have the viral E6 and E7 proteins, now encoded on genes integrated into the main chromosomes of the cells themselves rather than in a freestanding viral genome. In recent years several people have used RNA-interference to shut down the expression of the E6 and E7 genes and oddly enough this appears to reverse the cancer-phenotype of these cells. They slow down, stop dividing and eventually just die on their own. This despite over 50 years of in vitro culturing opportunities to pick up additional growth-promoting mutations. ''Interesting. But I wouldn't call that "oddly enough"; this seems compatible with viral origin theories.'' Well certainly Henrietta Lack's cancer was viral in origin. The "oddly enough" part is that in general inactivation of p53 alone is insufficient to transform a cell to a cancerous state so the reactivation of p53 would seem unlikely to be sufficient to transform the cell back to a non-cancerous state. ---- To be fair, I can imagine a scenario that sabotages the viral hypothesis I've been defending: one can imagine that tumor cells are behaving similarly to how they did during the first 3/4 of the 4 billion year evolution they've gone through, and that the damage from radiation, poisons, viruses, or whatever, are breaking the evolutionarily-new mechanisms that were causing them to behave symbiotically, so '''of course''' they revert to acting independently and/or parasitically. Ah...in adding this, I see someone mentioned this above, and I missed it earlier. I don't find that completely believable, though, because too many of their characteristics are indeed evolved parasitic abilities that they would not have had as single celled free organisms. Angiogenesis perhaps being the most dramatic such example. -- dm * Don't think of it as cancer cells (d)evolving towards freestanding organisms, but rather as dedifferentiating back towards the embryonic stem cells from which they were ultimately originally derived. In this context the ability to recruit new blood supply makes perfect sense. In general cancer prognosis correlates with how differentiated the tumor cells are, that is, cancers with more poorly differentiated cells (more embryonic-like) have a poorer prognosis. Obviously this analogy is not comprehensive, but is useful as a way to start to get a handle on the general process of carcinogenesis. How many, and how reliably? If there's a constellation of effects, then it would make simple reversion unlikely. At the moment, though, angiogenesis is the only trait listed here that wouldn't have been present in an amoeba (some of which are very close relatives of animals, e.g. ''Nuclearia'', and some of which are generally free-living but act as successful parasites once inside someone, e.g. ''Acanthamoeba''). If it's something that could be caused by a single hormone, it could be coincidence, especially if it's only present in some cancers. Speaking of which, are we supposing all cancers share an origin from the same virus, and if not, shouldn't they should differences in such traits anyways? A quick search, btw, suggests something which should have been obvious: that the tumor cells could develop abilities such as angiogenesis by mutation after they become free-agents, and are quickly selected for it. The comment above on stem cells makes good sense, too. Other finds give reasons to suspect the viral cause is flawed - for instance, cells in chemical induced tumors supposedly do not show a common genetic signature, which would be expected were they all infected by a common agent. Figures show up saying that 10-20% of cancers are viral, but there doesn't seem to be too much certainty in those. ''Hmm. This is all very interesting and reasonably persuasive. More vague, though; we still need to learn more about differentiation. -- dm'' ---- See also: DeoxyriboNucleicAcid